Frontline Science: Mast cells regulate neutrophil homeostasis by influencing macrophage clearance activity

Abstract

The receptor tyrosine kinase cKit and its ligand stem cell factor are essential for mast cells (MC) development and survival. Strains with mutations affecting the Kit gene display a profound MC deficiency in all tissues and have been extensively used to investigate the role of MC in both physiologic and pathologic conditions. However, these mice present a variety of abnormalities in other immune cell populations that can affect the interpretation of MC‐related responses. C57BL/6 KitW‐sh are characterized by an aberrant extramedullary myelopoiesis and systemic neutrophilia. MC deficiency in KitW‐sh mice can be selectively repaired by engraftment with in vitro‐differentiated MC to validate MC‐specific functions. Nevertheless, the impact of MC reconstitution on other immune populations has never been evaluated in detail. Here, we specifically investigated the neutrophil compartment in primary and secondary lymphoid organs of C57BL/6 KitW‐sh mice before and after MC reconstitution. We found that, albeit not apparently affecting neutrophils phenotype or maturation, MC reconstitution of KitW‐sh mice restored the number of neutrophils at a level similar to that of wild‐type C57BL/6 mice. In vitro and ex vivo experiments indicated that MC can influence neutrophil clearance by increasing macrophages’ phagocytic activity. Furthermore, the G‐CSF/IL‐17 axis was also influenced by the presence or absence of MC in KitW‐sh mice. These data suggest that MC play a role in the control of neutrophil homeostasis and that this aspect should be taken into account in the interpretation of results obtained using KitW‐sh mice.

MASTers of neutrophil homeostasis

“…Jachetti et al report that MCs control the abundance of neutrophils. 2 The elevated numbers of Ly6G hi neutrophils in the spleen and blood in the Kit W-sh mice are reduced to the wild-type levels by reconstituting the Kit W-sh mice with wild-type bone marrow-derived mast cells, illustrating an important and previously unrecognized mechanism of control of neutrophil homeostasis ( Fig. 1).…”

“…and published in the current issue of the Journal of Leukocyte Biology. 2 Neutrophils are remarkably short-lived cells at steady state with a circulating half-life of 6 to 8 h and are produced at an impressive rate of 5×10 10 to 10 × 10 10 cells/day. 3 The frequencies of circulating neutrophils are tightly controlled by the coordinated regulation of granulopoiesis, mobilization from the bone marrow, and clearance.…”

“…Mechanistically, MCs did not alter neutrophil maturation status or ability to respond to activation signals, but influenced macrophages’ ability to phagocytose neutrophils . This effect was neutrophil specific, as macrophage phagocytosis of apoptotic B cells in vitro was not altered in coculturing experiments where MC‐activated macrophages were challenged with apoptotic B cells.…”

“…The issue has been investigated by Jachetti et al. and published in the current issue of the Journal of Leukocyte Biology …”

“…Reconstitution of Kit W‐sh mice with BM MCs reduced circulatory granulocyte colony stimulating factor (G‐CSF) levels, implicating MC‐driven feedback control on granulopoiesis (Fig. ).…”